T细胞调控基因CD274（PD-L1）及TNFRSF14异常通过T/B细胞相互作用促进甲状腺粘膜相关结外边缘区（MALT）淋巴瘤发病的机制研究

近年来，肿瘤免疫治疗尤其是PD-1/PD-L1抑制剂应用广泛；然而值得注意的是，我们前期研究提示PD-1/PD-L1轴抑制可能促进甲状腺粘膜相关结外边缘区（MALT）淋巴瘤的发生发展。我们发现，76%的甲状腺MALT淋巴瘤携带T细胞调控基因CD274（编码PD-L1）和TNFRSF14突变/拷贝数缺失，主要为失活性改变，且与CD4+肿瘤浸润T细胞过度活化相关；由此推测上述异常破坏T细胞负性调控，从而促进B细胞增殖、生存和恶性转化。本项目拟：1.通过临床标本和细胞实验研究CD274突变对PD-L1和下游通路及T细胞调控的影响；2.体内水平探究CD274和TNFRSF14基因异常对肿瘤浸润T细胞和T/B细胞相互作用的影响，进而揭示甲状腺MALT淋巴瘤发病机制。MALT淋巴瘤作为研究免疫与遗传学异常共同致病的范本，其发病机制的阐明有助于肿瘤的早期预防和肿瘤免疫治疗的发展。

Tumor immunotherapy becomes more and more widely used, especially PD-1/PD-L1 inhibitors. However, our previous study suggested that PD-1/PD-L1 axis inhibition may promote thyroid mucosal associated extranodal marginal zone (MALT) lymphoma. We found that 76% thyroid MALT lymphoma cases carried abnormalities in T-cell regulatory genes, including CD274 (encoding PD-L1) mutations/copy number deletion and TNFRSF14 mutations, which was associated with over-activated tumor-infiltrating T-cells. These may promote B-cell proliferation and transformation through exaggerative T-cell help. Here we aim to further investigate the functional changes of CD274 and TNFRSF14 mutation/deletion on T-cell regulation and T/B-cell interaction, and to reveal the pathogenesis of thyroid MALT lymphoma. This project intends to: (1) Demonstrate how these genetic alterations affect the receptor expression and downstream pathways in thyroid MALT lymphoma using clinical specimens and in vitro experiment; (2) Study the effects on tumor-infiltrating T-cells, and how these changes drive tumorigenesis through T/B-cell interaction in vivo. The implementation of this project reveals the functional changes of CD274 mutations for the first time, which is helpful for the study of tumor pathogenesis and brings thinking to PD-1/PD-L1 immunotherapy.